1. Field of the Invention
This invention relates to the chemistry and biology of compounds with immunosuppressive and lymphocyte homing activities and, more specifically, this invention relates to methods and comprises compositions for accelerating lymphocyte homing in a mammal.
2. Description of Related Art
In general, compounds used to suppress the immune response attack certain immune cells. By either removing these cells from the immune system or hampering their ability to respond to chemical messengers, the number of cells participating in any immune response decreases. With fewer cells responding, the immune system cannot mount the same response reaction. The result is immunosuppression.
The use of these compounds follows directly from our understanding of the immune response and the function of immune cells. Numerous publications in the art describe the molecular and cellular aspects of the immune response. Generally, the immune system responds to an antigen first by processing and presenting the antigen through antigen presenting cells (APCs). Over the last decade, intensive research has resulted in a deep and detailed knowledge of this process at the molecular level (1-3). Following the APCs action are the T lymphocytes or T cells. Activated by a process involving antigen presentation by the APC, T cells then initiate the development of a variety of effector immune cells. The activities of phagocytes, natural killer cells, cytotoxic T cells, and B cells and other effector cells each arise from the cytokines secreted from activated T cells. The cytokines, then, are the chemical messengers that trigger the immune response mechanisms that the effector cells perform.
By killing or modifying the cells or messengers of the immune system, certain compounds can be used as treatments and therapies for suppressing the immune response. Our understanding of the immune response has led to two general groups of immunosuppressive compounds, those compounds effecting cytokine action and those directly effecting immune cell metabolism and activity.
In the first group are cyclosporin A (CsA), tacrolimus (TRL) and rapamycin (4-5). CsA, a cyclic peptide, is produced from the Trichoderma polysporum fungus (6-7). TRL, or FK-506, is a macrolide from Streptomyces tsukubaensis (8-10). These compounds cut out the cytokine messengers of the immune response by preventing their synthesis. The immune effector cells, therefore, cannot be recruited to complete the immune response. Rapamycin, on the other hand, blocks the cytokine signal from effecting the immune cells (34).
More specifically, CsA suppresses the immune response by inhibiting production of the cytokine interleukin 2 (IL-2) in antigen-stimulated helper T cells, a subset of T cells. TRL inhibits antigen-induced T cell proliferation by inhibiting IL-2 production in helper T cells. CsA and TRL act by binding to two different proteins (11), called cyclophilin and FKBP respectively. After the binding, both of the CsA/cyclophilin and TRUFKBP complexes inhibit the phosphatase activity of a protein called calcineurin, which activates nuclear factor (NF-AT) in activated T cells. NF-AT promotes IL-2 gene transcription and thus IL-2 production. However, when the CsA/cyclophilin and TRLUFKBP complexes inhibit activation of NF-AT, production of IL-2 is also inhibited.
Since CsA and TRL have almost the same mechanism of action, these drugs also show quite similar side effects, such as renal and liver toxicity (12). Multiple drug therapies with either CsA or TRL, using steroids or other immunosuppressants such as azathioprine and mizoribine (13-14), were widely used in order to reduce the side effects of individual immunosuppressants. However, the similar side effects of CsA and TRL prohibits their use together. New immunosuppressant compounds should not only be highly safe but should also possess a mechanism of action distinct from CsA and TRL so that they can be concomitantly administered.
Compounds from the second group of similarly-acting chemicals each interfere with nucleoside synthesis in the immune cells, arresting their metabolism and their immune activity. The group includes azathioprine (35), mizoribine (36), mycophenolic acid (37), and brequinar sodium (38). These compounds can also result in toxic side effects.
Researchers and clinicians use these compounds in human therapies. Those employing CsA have made great contributions to the prevention of acute rejection in human organ transplantation. Immunosuppressants are also used to treat autoimmune diseases, such as rheumatoid arthritis, and diseases such as psoriasis, atopic dermatitis, bronchial asthma, and pollinosis. However, because of the toxic side effects of the currently used compounds, new, more effective and less toxic methods to suppress the immune response are needed in the art.